Significant Functional Decline Research Articles

COVID-19 plasma induces subcellular remodelling within the pulmonary microvascular endothelium

BackgroundCOVID-19 caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can affect multiple organ systems, including the pulmonary vasculature. Endothelial cells (ECs) are thought to play a key role in the propagation of COVID-19, however, our understanding of the exact scale of dysregulation sustained by the pulmonary microvasculature (pMV) remains incomplete. Here we aim to identify transcriptional, phenotypic, and functional changes within the pMV induced by COVID-19. Methods and resultsHuman pulmonary microvascular endothelial cells (HPMVEC) treated with plasma acquired from patients hospitalised with severe COVID-19 were compared to HPMVEC treated with plasma from patients hospitalised without COVID-19 but with other severe illnesses. Exposure to COVID-19 plasma caused a significant functional decline in HPMVECs as seen by a decrease in both cell viability via the WST-1 cell-proliferation assay and cell-to-cell barrier function as measured by electric cell-substrate impedance sensing. High-content imaging using a Cell Painting image-based assay further quantified morphological variations within sub-cellular organelles to show phenotypic changes in the whole endothelial cell, nucleus, mitochondria, plasma membrane and nucleolus morphology. RNA-sequencing of HPMVECs treated with COVID-19 plasma suggests the observed phenotype may, in part, be regulated by genes such as SMAD7, BCOR, SFMBT1, IFIT5 and ZNF566 which are involved in transcriptional regulation, protein monoubiquitination and TGF-β signalling. Conclusion and impactDuring COVID-19, the pMV undergoes significant remodelling, which is evident based on the functional, phenotypic, and transcriptional changes seen following exposure to COVID-19 plasma. The observed morphological variation may be responsible for downstream complications, such as a decline in overall cellular function and cell-to-cell barrier integrity. Moreover, genes identified through bulk RNA sequencing may contribute to our understanding of the observed phenotype and assist in developing strategies that can inform the rescue of the dysregulated endothelium.

Assessment of the upper limb function, strength, and mobility in treatment-naive children with spinal muscular atrophy Types 2 and 3.

Current upper limb assessments in pediatric spinal muscular atrophy (SMA) may not adequately capture change with disease progression. Our aim was to examine the relationship between motor function, strength, and hand/finger mobility of the upper limb in treatment-naïve children with SMA Types 2 and 3 to assess new methods to supplement current outcomes. The Revised Upper Limb Module (RULM), grip and pinch strength, and hand/finger mobility data were collected from 19 children with SMA Types 2 and 3 aged 5.2-16.9 years over a year. A median loss between 0.5 and 2.5 points in the RULM was seen across all SMA subgroups with the biggest median loss recorded between 10 and 14 years of age. The grip strength loss was -0.06 kg (-4.69 to 3.49; IQR, 1.21); pinch improvement of 0.05 (-0.65 to 1.27; IQR, 0.48); hand/finger mobility test improvement of 4 points (-24 to 14; IQR, 6.75) for the whole cohort. Significant correlations were found between the RULM and grip strength (p < .001), RULM and pinch strength (p < .001), RULM and revised Brooke (p < .001), grip strength and pinch strength (p < .001). The combined use of the RULM, dynamometry, and hand mobility provide insight about correlations between function and strength in children with SMA. The RULM and grip strength assessments captured a significant decline in upper limb function, whereas the pinch and finger/hand mobility showed an improvement over the course of 1 year and these results should be considered for future studies.

Joint effect of abnormal systemic immune-inflammation index (SII) levels and diabetes on cognitive function and survival rate: A population-based study from the NHANES 2011-2014.

The purpose of this study was to investigate whether the combination of abnormal systemic immune-inflammation index (SII) levels and hyperglycemia increased the risk of cognitive function decline and reduced survival rate in the United States. This cross-sectional study used data from the National Health and Nutrition Examination Survey (NHANES) database from 2011-2014 and enrolled 1,447 participants aged 60 years or older. Restricted cubic splines (RCS), linear regression and kaplan-meier(KM) curve were employed to explore the combined effects of abnormal SII and hyperglycemia on cognitive function and survival rate, and subgroup analysis was also conducted. The RCS analysis revealed an inverted U-shaped relationship between lgSII levels and cognitive function. Linear regression analysis indicated that neither abnormal SII nor diabetes alone significantly contributed to the decline in cognitive function compared to participants with normal SII levels and blood glucose. However, when abnormal SII coexisted with diabetes (but not prediabetes), it resulted to a significant decline in cognitive function. After adjusting for various confounding factors, these results remained significant in Delayed Word Recall (β:-0.76, P<0.05) and Digit Symbol Substitution tests (β:-5.02, P<0.05). Nevertheless, these results showed marginal significance in Total Word Recall test as well as Animal Fluency test. Among all subgroup analyses performed, participants with both abnormal SII levels and diabetes exhibited the greatest decline in cognitive function compared to those with only diabetes. Furthermore, KM curve demonstrated that the combination of abnormal SII levels and diabetes decreased survival rate among participants. The findings suggest that the impact of diabetes on cognitive function/survival rate is correlated with SII levels, indicating that their combination enhances predictive power.

Microfluidic approach to correlate C. elegans neuronal functional aging and underlying changes of gene expression in mechanosensation.

The aging process has broad physiological impacts, including a significant decline in sensory function, which threatens both physical health and quality of life. One ideal model to study aging, neuronal function, and gene expression is the nematode Caenorhabditis elegans, which has a short lifespan and relatively simple, thoroughly mapped nervous system and genome. Previous works have identified that mechanosensory neuronal structure changes with age, but importantly, the actual age-related changes in the function and health of neurons, as well as the underlying genetic mechanisms responsible for these declines, are not fully understood. While advanced techniques such as single-cell RNA-sequencing have been developed to quantify gene expression, it is difficult to relate this information to functional changes in aging due to a lack of tools available. To address these limitations, we present a platform capable of measuring both physiological function and its associated gene expression throughout the aging process in individuals. Using our pipeline, we investigate the age-related changes in function of the mechanosensing ALM neuron in C. elegans, as well as some relevant gene expression patterns (mec-4 and mec-10). Using a series of devices for animals of different ages, we examined subtle changes in neuronal function and found that while the magnitude of neuronal response to a large stimulus declines with age, sensory capability does not significantly decline with age; further, gene expression is well maintained throughout aging. Additionally, we examine PVD, a harsh-touch mechanosensory neuron, and find that it exhibits a similar age-related decline in magnitude of neuronal response. Together, our data demonstrate that our strategy is useful for identifying genetic factors involved in the decline in neuronal health. We envision that this framework could be applied to other systems as a useful tool for discovering new biology.

Post-operative rehabilitation after surgical shoulder stabilization with Latarjet procedure: a study protocol for systematic scoping review

Background: Anterior shoulder instability (ASI) is highly prevalent in the general population causing a significant functional decline and increased healthcare burden. Among the surgical stabilization options, the Latarjet procedure is commonly preferred to treat traumatic ASI in young active individuals. Despite the advances in surgical procedures, the research evidence regarding the content of post-operative rehabilitation programmes following a Latarjet procedure for ASI is inconclusive. Methods: This protocol will adhere on the preferred reporting items for systemic reviews and meta-analyses extension for scoping reviews (PRISMA-ScR) and the Joanna Briggs Institute guidelines. MEDLINE, OvidSP, Embase, Cochrane Library, CINAHL, PubMed, SPORTS Discus and Scopus databases will be searched for relevant studies. Two reviewers will independently screen the results against the eligibility criteria defined by the population concept and context of this scoping review. A PRISMA-ScR flow diagram will be used to present the number of sources of evidence identified. The two reviewers will extract the data aiming to synthesize the results in appropriate tables. The most relevant details of the post-operative rehabilitation programmes will be presented based on consensus on exercise reporting template checklist. Conclusions: This scoping review can provide critical information regarding the content of the post-operative rehabilitation programmes after shoulder stabilization with a Latarjet procedure in patients with ASI.

Ketorolac in neonates and infants following congenital heart surgery: a retrospective review.

Pain management is essential in the immediate post-surgical period. We sought to describe the ketorolac dose regimen in neonates and infants following cardiac surgery. Secondary outcomes included renal dysfunction, bleeding, and pain management. We performed a single-centre retrospective cohort study of neonates and infants (aged < 12 months) who received ketorolac following cardiac surgery, from November 2020 through November 2021 (inclusive). Ketorolac was administered at 0.5 mg/kg every 6 hours. Safety was defined by absence of a clinically significant decline in renal function (i.e., increase in serum creatinine [SCr] by ≥ 0.3 mg/dL from baseline within 48 hours and/or urine output ≤ 0.5 mL/kg/hour for 6 hours) and absence of clinically significant bleeding defined as major by International Society on Thrombosis and Hemostasis paediatric criteria or Severe/Fatal Bleeding Events by Nellis et al. Efficacy measures included pain scores and opioid utilisation. Fifty-five patients met eligibility criteria. The median (range) dose and duration of ketorolac administration was 0.5 mg/kg/dose for 48 (6-90) hours. Among all patients, there was not a statistically significant difference observed in median SCr within 48 hours of baseline (p > .9). There were no major or severe bleeding events. The median (range) opioid requirements (morphine intravenous equivalents per kg per day) at 48 hours post-ketorolac initiation was 0.1 (0-0.8) mg/kg/day. If validated prospectively, these findings suggest that a ketorolac regimen 0.5 mg/kg/dose every 6 hours in neonates and infants post-cardiac surgery may be safe with regard to renal function and bleeding risk, and effective regarding opioid-sparing capacity.

Review of effects of respiratory muscle training on athlete performance

For a long time, the respiratory system plays an important role in athletes' training and competition, and its quality directly affects the athletes' competitive level and state. In particular, after the COVID-19 pandemic, many athletes have experienced a significant decline in respiratory function due to viral infection, which has led to a renewed understanding of the importance of respiratory function in athlete training. Furthermore, respiratory muscle training can be a key to improving respiratory function. This paper will review the effects of respiratory muscle training on athlete performance by means of comparative analysis. After analyzing and organizing 36 articles, it can be concluded that different functions of respiratory muscles can improve the sports performance of different types of athletes. Among them, the exercise of inspiratory muscles is the most important, even for athletes infected with COVID-19.

The functional trajectories of older women having surgery for gynaeoncology cancer: A single site prospective observational study

IntroductionPopulation aging longevity and advances in robotic surgery suggest that increasing numbers of older women having gynaeoncological surgery is likely. Postoperative morbidity and mortality are more common in older than younger women with the age-associated characteristics of multimorbidity and frailty being generally predictive of worse outcome. Priorities that inform treatment decisions change during the life course: older patients often place greater' value on quality-of-life-years gained than on life expectancy following cancer treatments. However, data on post-operative cognition, frailty, or functional independence is sparse and not routinely collected. This study aimed to describe the clinical characteristics and trajectory of functional change of older women in the 12 months following gynaeoncological surgery and to explore the associations between them. Materials and MethodsThe prospective observational cohort study recruited consecutive women aged 65 or over scheduled for major gynaeoncologic surgery between July 2017 and April 2019. Baseline data on cancer stage, multimorbidity, and geriatric syndromes including cognition, frailty, and functional abilities were collected using standardised tools. Delirium and post-operative morbidity were recorded. Post hospital assessments were collected at 3-, 6-, and 12-months. ResultsOverall, of 103 eligible participants assessed pre-operatively, most (77, 70%) remained independent in personal care at all assessments from discharge to 12 months. Functional trajectories varied widely over the 12 months but overall there was no significant decline or improvement for the 85 survivors. Eleven experienced a clinically significant decline in function at six months. This was associated with baseline low mood (P < 0.05), albeit with small numbers (6 of 11). Cognitive impairment and frailty were associated with lower baseline function but not with subsequent functional decline. DiscussionThere was no clear clinical profile to identify the minority of older adults who experienced a clinically significant decline six months after surgery and for most, the decline was transient. This may be helpful in enabling informed patient consent. Assessment for geriatric syndromes and frailty may improve individual care but our findings do not indicate criteria for segmenting the patient population for selective attention. Future work should focus on causal pathways to potentially avoidable decline in those patients where this is not determined by the cancer itself.

Adenine model of chronic renal failure in rats to determine whether MCC950, an NLRP3 inflammasome inhibitor, is a renopreventive

BackgroundChronic renal failure (CRF) is defined by a significant decline in renal function that results in decreased salt filtration and inhibition of tubular reabsorption, which ultimately causes volume enlargement. This study evaluated the potential renopreventive effects of the NLRP3 inflammasome inhibitor MCC950 in adenine-induced CRF in rats due to conflicting evidence on the effects of MCC950 on the kidney.MethodsSince the majority of the kidney tubular abnormalities identified in people with chronic renal disease are comparable to those caused by adding 0.75 percent of adenine powder to a rat's diet each day for four weeks, this method has received broad approval as a model for evaluating kidney damage. Throughout the test, blood pressure was checked weekly and at the beginning. Additionally, oxidative stress factors, urine sample examination, histological modifications, and immunohistochemical adjustments of caspase-3 and interleukin-1 beta (IL-1) levels in renal tissues were carried out.ResultsResults revealed that MCC950, an inhibitor of the NLRP3 inflammasome, had a renopreventive effect, which was demonstrated by a reduction in blood pressure readings and an improvement in urine, serum, and renal tissue indicators that indicate organ damage. This was also demonstrated by the decrease in neutrophil gelatinase-associated lipocalin tubular expression (NGAL).The NLRP3 inflammasome inhibitor MCC950 was found to significantly alleviate the worsening renal cellular alterations evidenced by increased expression of caspase-3 and IL-1, according to immunohistochemical tests.ConclusionThe NLRP3 inflammasome inhibitor MCC950 demonstrated renopreventive effects in the CRF rat model, suggesting that it might be used as a treatment strategy to stop the progression of CRF.

Epigenetic Mechanisms in Hematologic Aging and Premalignant Conditions.

Hematopoietic stem cells (HSCs) are essential for maintaining overall health by continuously generating blood cells throughout an individual's lifespan. However, as individuals age, the hematopoietic system undergoes significant functional decline, rendering them more susceptible to age-related diseases. Growing research evidence has highlighted the critical role of epigenetic regulation in this age-associated decline. This review aims to provide an overview of the diverse epigenetic mechanisms involved in the regulation of normal HSCs during the aging process and their implications in aging-related diseases. Understanding the intricate interplay of epigenetic mechanisms that contribute to aging-related changes in the hematopoietic system holds great potential for the development of innovative strategies to delay the aging process. In fact, interventions targeting epigenetic modifications have shown promising outcomes in alleviating aging-related phenotypes and extending lifespan in various animal models. Small molecule-based therapies and reprogramming strategies enabling epigenetic rejuvenation have emerged as effective approaches for ameliorating or even reversing aging-related conditions. By acquiring a deeper understanding of these epigenetic mechanisms, it is anticipated that interventions can be devised to prevent or mitigate the rates of hematologic aging and associated diseases later in life. Ultimately, these advancements have the potential to improve overall health and enhance the quality of life in aging individuals.

Prevalence of Cognitive Domain Impairments in Mild Cognitive Impairment Subtypes in the NACC Database

AbstractBackgroundMild cognitive impairment (MCI) reflects cognitive deficits without significant functional decline in activities of daily living. MCI subtypes correspond to phenotypic cognitive impairment patterns in memory, attention, language, executive, and visuospatial compared to age‐adjusted norms: Amnestic single domain (ASD) or multi‐domain (AMD), Nonamnestic single domain (NASD), or Nonamnestic multi‐domain (NAMD. In this study, we explore frequencies of domain impairment by MCI subtype, and frequency of each combination of (memory ±) all combinations of Language, Attention, Executive and Visuospatial impairment in the NACC database. This is of practical importance for both localization of amyloid or tau deposition as well as relative localization of areas of deficit.MethodUsing the National Alzheimer’s Coordinating Center (NACC) database (grant U24 AG072122), we selected all initial Uniform Data Set (UDS) assessments diagnosed as MCI with sub‐typing. The NACC data was collected from 37 participating Alzheimer’s disease Research Centers. 9852 individuals with MCI on baseline UDS visits were analyzed: 45.4% AMD, 33.7% ASD, 12.6% NASD, 8.2% NAMD.ResultFigure one shows the distribution overall of domain specific impairment by MCI subtype. Except for ASD, Executive function was the most common domain affected, and visuospatial was the least common. NAMD had higher percentages affected for all domains compared to AMD. In Figure 2, all combinations of language, executive, attention and visuospatial are compared. The most frequent combination was Language‐Executive, and the least common combination was Language‐Attention‐Visuospatial. The mean absolute percentage difference between AMD and NAMD was 2.2%. The Spearman’s rho of AMD vs. NAMD was 0.845.ConclusionWithin an MCI subtype, there is substantial variability in the frequency of individual domains. However, comparison of AMD and NAMD shows striking uniformity in frequency of combinations of individual domains with very correlation. The latter findings suggests that Amnestic and Nonamnestic multidomain subtypes may be closely related in pathophysiology but show greater heterogeneity within a MCI subtype.

Comparison of Baseline Cognitive Testing Results in Mild Cognitive Impairment Subtypes in the NACC Database

AbstractBackgroundMild cognitive impairment (MCI) reflects cognitive deficits without significant functional decline in activities of daily living. MCI subtypes correspond to phenotypic cognitive impairment patterns in memory, attention, language, executive, and visuospatial compared to age‐adjusted norms: Amnestic single domain (ASD) or multi‐domain (AMD), Nonamestic single domain (NASD), or Nonamnestic multi‐domain (NAMD). Previous studies have suggested Nonanmestic subtypes demonstrate more likely represent non‐AD prodromes, but conclusions have been limited by small sample sizes. The present study attempts to see correlates of htese proposed differences as evident by cognitive testing battery.MethodUsing the National Alzheimer’s Coordinating Center (NACC) database (grant U24 AG072122), we selected all initial Uniform Data Set (UDS) assessments diagnosed as MCI with subtyping. The NACC data was collected from 37 participating Alzheimer’s disease Research Centers. Baseline demographic, clinical features, Neuropsychiatric symptoms, and AD biomarkers were collected. One‐way ANOVA analyses were used to compare cognitive performance on all UDS cognitive tests across MCI subtypes.Result9852 individuals with MCI on baseline UDS visits were analyzed: 45.4% AMD, 33.7% ASD, 12.6% NASD, 8.2% NAMD. There were significant differences (P&lt;.001 or greater) on all measures which is not unexpected given large sample size. Notable differences between ASD/AMD, NASD/NAMD were prominent on Trails B, Craft story immediate and delayed recall, and Benton immediate recall minus delayed recall. See table for complete summary of scores.Trails B, mean (SD) times were ASD (113±62), AMD (157±82), NASD (143±78),NAMD (171±83). Craft story showed clear differences between groups on immediate recall (ASD14.9 (6.4)/AMD 14.2 (6.76)/NASD 18.0 (8.0/NAMD 17.9 (6.9)) and delayed recall (ASD 9.9 (7.0)/AMD 10.1 (6.7)/NASD 15.2 (6.4)/NAMD 15.5 (6.2)). Benton immediate minus delayed recall differences were ASD 8.1/AMD 7.9 versus NASD 4.2, NAMD 4.9)ConclusionNonamnestic MCI subtypes are characterized by lower performance on executive tasks such as Trails B. Conversely, memory tasks show lower performance in NACC UDS participants with amnestic subtypes of MCI. This would support the concept that Nonamnestic MCI may represent prodromal stages of non‐AD dementia more frequently.

Primary etiology and associated medical conditions in Mild Cognitive Impairment Subtypes in the NACC Database

AbstractBackgroundMild cognitive impairment (MCI) reflects cognitive deficits without significant functional decline in activities of daily living (1). MCI subtypes correspond to phenotypic cognitive impairment patterns in memory, attention, language, executive, and visuospatial compared to age‐adjusted norms: Amnestic single domain (ASD) or multi‐domain (AMD), Nonamnestic single domain (NASD), or Nonamnestic multi‐domain (NAMD). Previous studies have suggested nonamnestic subtypes are more likely to represent non‐AD prodromes, but conclusions have been limited by small sample sizes (1).MethodUsing the National Alzheimer’s Coordinating Center (NACC) database (grant U24 AG072122), we selected all initial Uniform Data Set (UDS) assessments diagnosed as MCI with subtyping. The NACC data was collected from 37 participating Alzheimer’s disease Research Centers. Baseline clinical features, primary etiology and associated medical conditions were collected.Results9852 individuals with MCI on baseline UDS visits were analyzed: 45.6% were diagnosed with AD (Table 1). AD was the most common primary etiology in all subtypes, more frequent in amnestic than nonamnestic subtypes (AMD 54.1%; ASD 50.5%; NAMD 20.0%; NASD 18.8%). Overall, 6% were diagnosed with DLB and 3.1% with PD; NAMD and NASD were more frequent than AMD or ASD. The most frequently associated medical conditions were hypercholesterolemia, HTN, depression, anxiety, sleep apnea and diabetes (table 2). The highest percentage of depression and anxiety were in nonamnetsic subtypes. Recent stroke was most frequent in NAMD.ConclusionMCI is a heterogeneous disorder, and its classification by subtypes is essential in understanding prodromal stages and neurodegenerative neuropathology. Dementia risk modulation and prevention is linked to identification and treatment of associated medical conditions including frequent neuropsychiatric comorbidity (2).

Evaluation of ECOG Performance Status at Diagnosis and Relapse in Patients with Acute Myeloid Leukemia

Background: Eastern Cooperative Oncology Group (ECOG) performance status (PS) is often utilized in treatment decision-making for patients with acute myeloid leukemia (AML). Patients with relapsed or refractory (R/R) disease have a particularly poor prognosis and require complex treatment decisions that utilize patient preference, genetic profile and PS. Currently, limited data exist on the trend of PS between initial diagnosis and R/R AML, and we aimed to characterize PS in R/R AML and its association with short and long term survival. Methods: We utilized an institutional database from the University of Washington/ Fred Hutchinson Cancer Center to retrospectively identify a subset of patients with AML or other high-grade myeloid neoplasms (≥10% blasts in blood or marrow at diagnosis) who received both induction and salvage chemotherapy for first relapse between January 1, 2008 and December 1, 2021. Salvage treatment was divided into high intensity (cytarabine greater than 1g/m 2/dose), intermediate intensity (7+3 or similar), reduced intensity (i.e., hypomethylating agents) or other (investigational agents not fitting into prior categories or supportive care alone). The McNemar test was used for matched-pair analysis of PS at two timepoints. The Kaplan-Meier method was used for analysis of overall survival (OS). Multivariable regression was used to evaluate associations with 4 week survival. Multivariable Cox regression was used for analysis of overall survival. All statistical analyses were performed using R 4.2.1 (2022). Results: We identified 160 patients with R/R disease. Patients with missing PS data (n=33) or otherwise not meeting inclusion criteria (n=20) were excluded (baseline characteristics of 107 patients in Table 1). No significant change was identified in PS at initial diagnosis versus R/R (PS≤1 71% vs 63%, p=0.19). More patients had the same PS at R/R disease (51.4%) as compared to initial diagnosis, though some had worse PS (27.1%), and others had better PS (25.2%). At initial diagnosis, patients with poor PS had similar induction chemotherapy intensity to those with good PS (PS≤1 treatment intensity: high: 42.1%, intermediate: 34.2%, reduced: 23.7%, other: 0%; PS≥2 treatment intensity: high: 38.7%, intermediate: 32.2%, reduced: 25.8%, other: 3.2% (p=0.55). At R/R disease, patients with poor PS were more likely to receive less intensive therapy (PS≤1 treatment intensity: high: 52.2%, intermediate:14.9%, reduced: 14.9%, other: 17.9%; PS≥2 treatment intensity: high: 27.5%, intermediate:7.5%, reduced:32.5%, other: 32.5% (p=0.001)). There was no correlation between PS at R/R disease and rate of complete remission without measurable residual disease (PS≤1 = 26.8%, PS≥2 =20%, p=0.49) or treatment failure (PS≤1 = 38.8%, PS≥2 =35%, p=0.84). The 4-week unadjusted mortality rate at R/R was 10.4% for patients with PS≤1, and 25.6% for patients with PS ≥2 (p=0.04). OS was longer in patients with good PS (PS≤1) at R/R disease (8.9 months vs 3.0 months). In multivariate analysis, poor ECOG (HR 2.13, 95% CI 1.09-4.17) was correlated with worse OS, while favorable ELN score (HR 0.43, 95% CI 0.19-0.99) and transplant (HR 0.29, 95% CI 0.17-0.49) were associated with improved OS. We did not find a significant association between age, gender, secondary status, or change in PS and OS in our preliminary analysis. Conclusions: We did not identify a significant change in PS in R/R disease. Our preliminary results suggest that poor PS at R/R was correlated with an increased 4-week mortality rate and worse OS. Interestingly, we did not find a significant difference in treatment intensity for patients with poor PS at initial presentation. In addition, at R/R disease, patients with good and poor PS had similar rates of treatment failure despite patients with good PS being treated with more intensive regimens. A limitation of our work is possible selection bias, as patients with significant functional decline may not have returned for evaluation at R/R disease. Further work is needed to identify if there is a meaningful association between change in PS and outcomes at R/R disease.

Reevaluating age restrictions of spinal metastasis surgery in elderly groups with over 2-year follow-up

This study aimed to compare and assess clinical outcomes of spinal metastasis with epidural spinal cord compression (MESCC) in patients aged 65–79 years and ≥ 80 years with an acute onset of neurological illness who underwent laminectomy. A second goal was to determine morbidity rates and potential risk factors for mortality. This retrospective review of electronic medical records at a single institution was conducted between September 2005 and December 2020. Data on patient demographics, surgical characteristics, complications, hospital clinical course, and 90-day mortality were also collected. Comorbidities were assessed using the age-adjusted Charlson comorbidity index (CCI). A total of 99 patients with an overall mean age of 76.2 ± 3.4 years diagnosed with MESCC within a 16-year period, of which 65 patients aged 65–79 years and 34 patients aged 80 years and older were enrolled in the study. Patients aged 80 and over had higher age-adjusted CCI (9.2 ± 2.1) compared to those aged 65–79 (5.1 ± 1.6; p < 0.001). Prostate cancer was the primary cause of spinal metastasis. Significant neurological and functional decline was more pronounced in the older group, evidenced by Karnofsky Performance Index (KPI) scores (80+ years: 47.8% ± 19.5; 65–79 years: 69.0% ± 23.9; p < 0.001). Despite requiring shorter decompression duration (148.8 ± 62.5 min vs. 199.4 ± 78.9 min; p = 0.004), the older group had more spinal levels needing decompression. Median survival time was 14.1 ± 4.3 months. Mortality risk factors included deteriorating functional status and comorbidities, but not motor weakness, surgical duration, extension of surgery, hospital or ICU stay, or complications. Overcoming age barriers in elderly surgical treatment in MSCC patients can reduce procedural delays and has the potential to significantly improve patient functionality. It emphasizes that age should not be a deterrent for spine surgery when medically necessary, although older MESCC patients may have reduced survival.

Electroacupuncture ameliorates cognitive impairment in APP/PS1 mouse by modulating TFEB levels to relieve ALP dysfunction

Recently, the underlying mechanisms of acupuncture on the effects of Alzheimer’s disease (AD) treatment have not been fully elucidated. Defects in ALP (autophagy-lysosomal pathway) and TFEB (transcription factor EB) play critical roles in AD. Our previous studies have demonstrated that electroacupuncture (EA) can ameliorate both β-amyloid (Aβ) pathology and cognitive function in APP/PS1 mice.However, the effects of EA on the expression of ALP and TFEB and their potential mechanisms require further investigation.Twenty-eight male APP/PS1 mice were randomly divided into Tg and Tg + EA groups, and 14 C57BL/6 mice served as the wild-type (WT) group. After 1 week of adaptation to the living environment, mice in the Tg + EA group were restrained in mouse bags and received manual acupuncture at Baihui (GV20) acupoint and EA stimulation at bilateral Yongquan (KI1) acupoints, using the same restraint method for WT and Tg groups. The intervention was applied for 15 min each time, every other day, lasting for six weeks.After intervention, the spatial learning and memory of the mice was assessed using the Morris water maze test.Hippocampal Aβ expression was detected by immunohistochemistry and ELISA. Transmission electron microscopy (TEM) was used to observe autophagic vacuoles and autolysosomes in the hippocampus. Immunofluorescence method was applied to examine the expression of TFEB in CA1 region of the hippocampus and the co-localization of CTSD or LAMP1 with Aβ. Western blot analysis was performed to evaluate the changes of LC3, p62, CTSD, LAMP1, TFEB and n-TFEB (nuclear TFEB) in the hippocampus.The findings of behavioral assessment indicated that EA alleviated the cognitive impairment of APP/PS1 mice. Compared with the WT group, the Tg group showed significant cognitive decline and abnormalities in ALP and TFEB function (P < 0.01 or P < 0.05). However, these abnormal changes were alleviated in the Tg + EA group (P < 0.01 or P < 0.05). The Tg group also showed more senile plaques and ALP dysfunction features, compared with the WT group, and these changes were alleviated by EA.In conclusion, this study highlights that EA ameliorated Aβ pathology-related cognitive impairments in the APP/PS1 model associated with ALP and TFEB dysfunction.

Somatic comorbidity and the progression of cognitive impairment.

There are usually multiple factors underlying dementia in old age. Somatic comorbidity is one important element that influences the progression of cognitive impairment. The goal of this study was to assess the relationship between the progression of cognitive impairment and the presence and severity of comorbidities based on a four-year observation. Out of 128 patients from the Clinic for Outpatients in Gdansk, who were recruited into the study based on the criteria of the Working Group on Mild Cognitive Impairment, a total of 93 participants completed the four-year observation. Only the data from participants who completed the full period of observations were analysed. The mean age of the group was M = 75.93 (SD = 9.43). The level of progression of cognitive impairment was measured using the Clinical Dementia Rating Scale - Sum of Boxes, the severity of comorbidities was measured using the modified Cumulative Illness Rating Scale, and, additionally, at the time of inclusion in the study, participants were assessed using the MMSE scale and the Activity Scale, and sociodemographic data were collected. The Generalized Estimating Equations method was employed to fit a marginal model for analyzing the data collected in a repeated measures design. The tested model elucidated the role of the overall severity of comorbidities in explaining the progression of cognitive impairment, while controlling for everyday activity and basic demographic variables. During the four-year observation, a significant decline in cognitive function (B = 1.86, p < 0.01) was observed in the examined sample. The statistical analysis revealed that individuals with higher overall severity of comorbidities exhibited significantly more pronounced progression of cognitive impairment over time. Regarding particular comorbidities, metabolic diseases were found to be associated with a poorer prognosis (rho = 0.41, p < 0.05). Furthermore, a time physical activity interaction was identified as predicting cognitive impairment, indicating that individuals who were more physically active at the beginning of the study exhibited significantly less pronounced progression of cognitive impairment over the course of the 4 years. This study suggests the important roles of comorbidities and physical activity for the prognosis of mild cognitive impairment.

Manual Therapy and Exercise Have Similar Outcomes to Corticosteroid Injections in the Management of Patients With Subacromial Pain Syndrome: A Systematic Review and Meta-Analysis.

Subacromial pain syndrome (SAPS) is the most frequent diagnosis in patients with shoulder pain presenting with persistent pain and significant functional decline. Although exerciseand manual therapy (EMT) and corticosteroid injections provide first-line treatment options, evidence for the best management of SAPS remains inconclusive. We aimed to evaluate the effectiveness of EMT compared with corticosteroid injections on disability, recovery rates, and pain in patients with SAPS through a systematic review and meta-analysis approach. PubMed, Cumulative Index to Nursing and Allied Health Literature (CINAHL), Physiotherapy Evidence Database (PEDro), ScienceDirect, the Cochrane Library, and grey literature databases were searched. Only randomized controlled trials evaluating the effectiveness of EMT alone or as an additive intervention compared to corticosteroid injections were included. Methodological quality was evaluated with the PEDro score and certainty of evidence with the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach. In total, 8 trials with 946 patients were included. EMT presented no difference in disability compared with corticosteroid injections at very short- (standardized mean difference {SMD}: 0.19; 95%CI: -0.20, 0.58), short- (SMD: -0.16; 95%CI: -0.58, 0.25), mid- (SMD: -0.14; 95%CI: -0.44, 0.16), and long-term (SMD: 0.00; 95%CI: -0.25, 0.25) follow-up. No difference was found between the comparators in self-perceived recovery at very short- (risk ratio: 0.93; 95%CI: 0.71, 1.21) and mid- (risk ratio: 0.98; 95%CI: 0.90, 1.07) follow-up and in pain rating at very short- (SMD: -0.18; 95%CI: -0.73, 0.38), short- (SMD: 0.05; 95%CI: -0.26, 0.37), and long-term (SMD: 0.04; 95%CI: -0.26, 0.34) follow-ups. The addition of corticosteroid injections to EMT provided no better results in shoulder disability compared with EMT (SMD: 0.45; 95%CI: -0.47, 1.37) or corticosteroid injections alone (MD: 2.70; 95%CI: -7.70, 13.10) in the mid-term. Based on very low to moderate certainty of evidence, EMT has similar effects to corticosteroid injections on improving all outcomes in patients with SAPS at all follow-up periods. Based on low certainty of evidence the combination of both interventions does not change the treatment outcome compared with each intervention alone.

Predicting autosomal dominant polycystic kidney disease progression: review of promising Serum and urine biomarkers.

Autosomal dominant polycystic kidney disease (ADPKD) is one of the leading causes of end-stage renal disease. In spite of the recent tremendous progress in the understanding of ADPKD pathogenesis, the molecular mechanisms of the disease remain incompletely understood. Considering emerging new targeted therapies for ADPKD, it has become crucial to disclose easily measurable and widely available biomarkers for identifying patients with future rapid disease progression. This review encompasses all the research with a shared goal of identifying promising serum or urine biomarkers for predicting ADPKD progression or response to therapy. The rate of the ADPKD progress varies significantly between patients. The phenotypic variability is only partly explained by the underlying genetic lesion diversity. Considering significant decline in kidney function in ADPKD is not usually evident until at least 50% of the parenchyma has been destroyed, conventional kidney function measures, such as glomerular filtration rate (GFR), are not suitable for monitoring disease progression in ADPKD, particularly in its early stages. Since polycystic kidney enlargement usually precedes the decline in GFR, height-adjusted total kidney volume (ht-TKV) has been accepted as an early biomarker for assessing disease severity in ADPKD patients. However, since measuring ht-TKV is time-consuming and observer-dependent, the identification of a sensitive and quickly measurable biomarker is of a great interest for everyday clinical practice. Throughout the last decade, due to development of proteomic and metabolomic techniques and the enlightenment of multiple molecular pathways involved in the ADPKD pathogenesis, a number of urine and serum protein biomarkers have been investigated in ADPKD patients, some of which seem worth of further exploring. These include copeptin, angiotensinogen, monocyte chemoattractant protein 1, kidney injury molecule-1 and urine-to-plasma urea ratio among many others. The aim of the current review is to provide an overview of all of the published evidence on potentially clinically valuable serum and urine biomarkers that could be used for predicting disease progression or response to therapy in patients with ADPKD. Hopefully, this review will encourage future longitudinal prospective clinical studies evaluating proposed biomarkers as prognostic tools to improve management and outcome of ADPKD patients in everyday clinical practice.

Post-acute sequelae of SARS-CoV-2 (PASC) in nursing home residents: A retrospective cohort study.

Post-acute sequelae of SARS-CoV-2 (PASC) describes a syndrome of physical and cognitive decline that persists after acute symptoms of infection resolve. Few studies have explored PASC among nursing home (NH) residents. A retrospective cohort study was conducted at two NHs in Michigan. COVID-positive patients were identified from March 21, 2020 to October 26, 2021. The comparison group were patients who lived at the same NH but who were never infected during the study period. Minimum Data Set was used to examine trajectories of functional dependence (Activity of Daily Living [ADL] composite score) and cognitive function (Brief Interview for Mental Status [BIMS]). Linear mixed-effects models were constructed to estimate short-term change in function and cognition immediately following diagnosis and over time for an additional 12 months, compared to pre-COVID and non-COVID trajectories and adjusting for sex, age, and dementia status. We identified 171 residents (90 COVID-19 positive, 81 non-COVID) with 719 observations for our analyses. Cohort characteristics included: 108 (63%) ≥ 80 yrs.; 121 (71%) female; 160 (94%) non-Hispanic white; median of 3 comorbidities (IQR 2-4), with no significant differences in characteristics between groups. COVID-19 infection affected the trajectory of ADL recovery for the first 9 months following infection, characterized by an immediate post-infection decrease in functional status post-infection (-0.60 points, p = 0.002) followed by improvement toward the expected functional trajectory sans infection (0.04 points per month following infection, p = 0.271). NH residents experienced a significant functional decline that persisted for 9 months following acute infection. Further research is needed to determine whether increased rehabilitation services after COVID-19 may help mitigate this decline.